Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections
Amandine Crequer, … , Jean-Laurent Casanova, Emmanuelle Jouanguy
Amandine Crequer, … , Jean-Laurent Casanova, Emmanuelle Jouanguy
Published August 1, 2012
Citation Information: J Clin Invest. 2012;122(9):3239-3247. https://doi.org/10.1172/JCI62949.
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Research Article Immunology

Human RHOH deficiency causes T cell defects and susceptibility to EV-HPV infections

Abstract

Epidermodysplasia verruciformis (EV) is a rare genetic disorder characterized by increased susceptibility to specific human papillomaviruses, the betapapillomaviruses. These EV-HPVs cause warts and increase the risk of skin carcinomas in otherwise healthy individuals. Inactivating mutations in epidermodysplasia verruciformis 1 (EVER1) or EVER2 have been identified in most, but not all, patients with autosomal recessive EV. We found that 2 young adult siblings presenting with T cell deficiency and various infectious diseases, including persistent EV-HPV infections, were homozygous for a mutation creating a stop codon in the ras homolog gene family member H (RHOH) gene. RHOH encodes an atypical Rho GTPase expressed predominantly in hematopoietic cells. Patients’ circulating T cells contained predominantly effector memory T cells, which displayed impaired TCR signaling. Additionally, very few circulating T cells expressed the β7 integrin subunit, which homes T cells to specific tissues. Similarly, Rhoh-null mice exhibited a severe overall T cell defect and abnormally small numbers of circulating β7-positive cells. Expression of the WT, but not of the mutated RHOH, allele in Rhoh–/– hematopoietic stem cells corrected the T cell lymphopenia in mice after bone marrow transplantation. We conclude that RHOH deficiency leads to T cell defects and persistent EV-HPV infections, suggesting that T cells play a role in the pathogenesis of chronic EV-HPV infections.

Authors

Amandine Crequer, Anja Troeger, Etienne Patin, Cindy S. Ma, Capucine Picard, Vincent Pedergnana, Claire Fieschi, Annick Lim, Avinash Abhyankar, Laure Gineau, Ingrid Mueller-Fleckenstein, Monika Schmidt, Alain Taieb, James Krueger, Laurent Abel, Stuart G. Tangye, Gérard Orth, David A. Williams, Jean-Laurent Casanova, Emmanuelle Jouanguy

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Figure 1

Homozygous RHOH loss-of-expression mutation in 2 patients with persistent EV-HPV infections.

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Homozygous RHOH loss-of-expression mutation in 2 patients with persisten...
(A) Pedigree of the family with susceptibility to EV-HPV infections and other infectious manifestations. Generations are designated by a Roman numeral (I, II, III, IV, and V). P1 and P2 are represented by black symbols. The proband is indicated by an arrow. The asterisk indicates the individuals genotyped with the Affymetrix Genome-Wide SNP 6.0 array. (B) Automated sequencing profile showing the Y38X RHOH mutation in genomic DNA (gDNA) extracted from EBV-B cells from the patients and comparison with the sequence obtained from a healthy control. (C) Schematic representation of the structure of the RHOH protein adapted from the work of Fueller et al. (17). Y38X is situated between the phosphate-binding loop and the ITAM-like domain. The 4 possible reinitiation sites downstream from the mutation are indicated by small black arrows. (D) RHOH mRNA production, as assessed by qRT-PCR on total RNA isolated from saimiri T cells from the 2 patients, 1 healthy sibling (S1), and the father (F), both heterozygous for the mutant allele, and 2 healthy controls (C1 and C2). Mean + SD for 3 experiments is presented for all samples except for P1 (2 experiments). (E) Immunoblot analyses of 30 μg of total protein extracted from the saimiri T cells of P1, P2, S1, F, C1, and C2, with an antibody directed against RHOH and an antibody against GAPDH as a protein-loading control. (F) Immunoblot analysis of NIH/3T3 cells transfected with WT RHOH, Y38X RHOH, or 139-C RHOH. NT, not transduced.